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JAC Advance Access originally published online on December 22, 2005
Journal of Antimicrobial Chemotherapy 2006 57(2):252-259; doi:10.1093/jac/dki436
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum

Santiago Ramón-García1, Carlos Martín1, José A. Aínsa1,* and Edda De Rossi2

1 Departamento de Microbiología, Medicina Preventiva y Salud Pública, Universidad de Zaragoza, 50009 Zaragoza, Spain; 2 Dipartimento di Genetica e Microbiologia, Università degli Studi di Pavia, 27100 Pavia, Italy

Received 2 August 2005; returned 8 September 2005; revised 27 October 2005; accepted 6 November 2005

* Corresponding author. Tel: +34-976-762420; Fax: +34-976-762604; E-mail: ainsa{at}unizar.es

Objectives: The aim of this study was to characterize the efflux pump Tap from Mycobacterium fortuitum, to test its sensitivity to well known efflux inhibitors, to study the interaction between tetracycline and these compounds and to test the ability of these compounds to overcome efflux pump-mediated tetracycline resistance. For all these studies, we produced Tap protein in Mycobacterium smegmatis.

Methods: Antibiotic susceptibility tests, tetracycline uptake/efflux experiments and chequerboard synergy tests.

Results: Tetracycline uptake/efflux experiments showed that Tap protein from M. fortuitum uses the electrochemical gradient across the cytoplasmic membrane to extrude tetracycline from the cell. This efflux activity is inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP) and reserpine, consistent with the decrease in MIC observed in antibiotic susceptibility testing in the presence of these inhibitors. Accumulation was not inhibited in experiments in which o-vanadate and chlorpromazine (CPZ) were tested. Inhibitor-treated cells used glycerol as a carbon source to re-establish the electrochemical gradient across the membrane and to restore efflux activity. CCCP, reserpine and CPZ reduced the MIC of tetracycline in the M. smegmatis strain expressing the Tap protein, whereas o-vanadate increased the MIC. We also observed synergy between tetracycline and CPZ or reserpine, and antagonism with o-vanadate.

Conclusions: The Tapfor efflux pump uses the electrochemical gradient to extrude tetracycline from the cell. This efflux activity can be inhibited by several compounds. This suggests that similar compounds could be used to overcome antibiotic resistance mediated by efflux pumps.

Keywords: tetracycline efflux , antibiotic resistance , mycobacteria , efflux pump inhibitors , synergy


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S. Ramon-Garcia, C. Martin, E. De Rossi, and J. A. Ainsa
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